1. Field of the Invention
The present invention is in the field of pharmacotherapy of nicotine-responsive neuropsychiatric disorders by administering a nicotine antagonist alone, particularly mecamylamine, or in combination with a neuroleptic agent. Examples of such disorders are schizophrenia, bipolar disorder, obsessive compulsive disorder, attention deficit hyperactivity disorder, Tourette's syndrome, and other movement disorders.
2. Background Information
Tourette's syndrome (TS) is an autosomal dominant neuropsychiatric disorder characterized by a range of symptoms, including multiple motor and phonic tics. It is a hyperkinetic movement disorder expressed largely by sudden, rapid, brief, recurrent, nonrhythmic, stereotyped motor movements (motor tics) or sounds (phonic tics), experienced as irresistible impulses but which can be suppressed for varying lengths of time (Tourette Syndrome Classification Study Group, Arch Neurol 50: 1013-16). Motor tics generally include eye blinking, head jerking, shoulder shrugging and facial grimacing, while phonic or vocal tics include throat clearing, sniffling, yelping, tongue clicking and coprolalia. The symptoms typically begin in childhood and range from relatively mild to very severe over the course of a patient's lifetime (Robertson M M, Br J Psychiatry, 154:147-169, 1989). Many TS patients also exhibit other neuropsychiatric abnormalities including obsessive compulsive symptoms (Pauls D L et al. Psychopharm Bull, 22:730-733, 1986), hyperactivity and attention deficits (Comings D E, Himes J A, Comings B G, J Clin Psychiatry, 51:463-469, 1990). Problems with extreme temper or aggressive behavior also are frequent (Riddle M A et al. Wiley Series in Child and Adolescent Mental Health, Eds. Cohen D J, Bruun, R D, Leckman J F, New York City, John Wiley and Sons, pp. 151-162, 1988; Stelf M E, Bornstein R A, Hammond L, A survey of Tourette syndrome patients and their families: the 1987 Ohio Tourette Survey, Cincinnati, Ohio Tourette Syndrome Association, 1988), as are school refusal and learning disabilities (Harris D, Silver A A, Learning Disabilities, 6(1):1-7, 1995; Silver A A, Hagin R A, Disorders of Learning Childhood, Noshpitz J D, ed. New York City: Wiley, pp. 469-508, 1990).
While the pathogenesis of TS is still unknown, excessive striatal dopamine and/or dopamine receptor hypersensitivity has been proposed (Singer H S et al. Ann Neurol, 12:361-366, 1982), based largely on the therapeutic effectiveness of dopamine receptor antagonists. T S is frequently treated with the dopamine antagonist haloperidol (Haldol.RTM., McNeil Pharmaceutical, Raritan, N.J.), which is effective in about 70% of cases (Erenberg G, Cruse R P, Rothner, A D, Ann Neurol, 22:383-385, 1987; Shapiro A K, Shapiro E, Wiley series in child and adolescent mental health, Eds. Cohen D J, Bruun R D, Leckman J F, New York City, John Wiley and Sons, pp. 267-280, 1988). Other neuroleptics include pimozide (Shapiro E S et al. Arch Gen Psychiatry, 46:722-730, 1989), fluphenazine (Singer H S, Gammon K, Quaskey S. Pediat Neuroscience, 12:71-74, 1985-1986), and risperidone (Stamenkovic et al., Lancet 344:1577-78, 1994). An alternative medication frequently employed is the .alpha.-adrenergic agonist clonidine, which also is effective for associated attention deficit hyperactivity disorder (ADHD) but has only a 40% success rate for motor and vocal tics (Bruun R D, J Am Acad Child Psychiatry, 23: 126-133, 1984; Cohen D J et al. Arch Gen Psychiatry 37: 1350-1357, 1980). Other medications that have been used with varying degrees of effectiveness include clonazepam (Gonce M, Barbeau A. Can J Neurol Sci 4:279-283, 1977), naloxone (Davidson P W et al. Appl Res Ment Retardation 4: 1-4, 1983) and fluoxetine (Riddle M A et al. J Am Acad Child Adol Psychiatry 29: 45-48, 1990). One of the most commonly used medications is haloperidol (Erenberg G, Cruse R P, Rothner A D, Ann Neurol, 22:383-385, 1987). However, therapeutic doses of haloperidol have frequent side effects that affect compliance, including difficulty in concentration, drowsiness, depression, weight gain, parkinsonian-like symptoms--and with long-term use--tardive dyskinesia (Shapiro A K, Shapiro E, Tourette's syndrome and Tic Disorders: Clinical Understanding and Treatment. Wiley series in child and adolescent mental health. Eds. Cohen, D J, Bruun, R D, Leckman J F, New York City, John Wiley and Sons, pp. 267-298, 1988). The side effect of tardive dyskinesia is particularly bothersome because it may add additional abnormal, involuntary movements of the tongue, jaw, trunk and/or extremities.
Erenberg et al. (Erenberg G, Cruse R P, Rothner A D, Ann Neurol 22:383-385, 1987) found that most patients with TS stop using their haloperidol or other neuroleptic medications by age 16, often because of these side effects. After TS patients quit medication because of the side effects, they have less control over speech and movement, which disqualify many for full-time, responsible jobs. The public, including law enforcement officers, often identify the symptoms as intoxication. The unexpected movements and coprolalia cause great social difficulties.
Systemic or intracaudate injections of nicotine have been found to profoundly potentiate reserpine-induced catalepsy in rats (Montgomery S P, Moss D E, Manderscheid P Z, Marijuana 84. Eds. Harvey D J, Paton W D M, Oxford, England, IRL Press, pp. 295-302, 1985; Moss D E et al, Life Sci 44: 1421-1525, 1989). Follow-up studies demonstrated that low doses of nicotine could also potentiate haloperidol-induced catalepsy in rats (Sanberg P R et al, Biomedicine and Pharmacotherapy 43: 19-23, 1989; Emerich D F, Norman A B, Sanberg P R, Psychopharmacol Bull 27(3): 385-390, 1991; Emerich D F et al, Pharmacol Biochem Behav 38: 875-880, 1991). These preclinical findings suggested that nicotine might also potentiate the therapeutic properties of neuroleptics in treating hyperkinetic movement disorders such as TS.
In a preliminary clinical trial, ten TS patients continued to receive haloperidol and added chewing Nicorette.RTM. nicotine (2 mg) gum. The patients had rapid, striking and marked relief from tics and other TS symptoms which were not optimally controlled by haloperidol alone (Sanberg P R et al, Biomedicine and Pharmacotherapy 43:19-23, 1989). In two subsequent studies, nicotine gum reduced tics in patients already receiving haloperidol, while placebo gum had no effect (McConville B J et al, Am J Psychiatry 148:793-794, 1991; McConville B J et al, Biological Psychiatry, 31:832-840, 1992). However, the benefits of the gum were short lived (1-4 hours), and the bitter taste and gastrointestinal side effects limited compliance (McConville B J et al, Biological Psychiatry 31:832-840, 1992).
The 7 mg, 24-hour transdermal nicotine patch (Nicoderm.RTM. TNP) was tested in 11 TS patients who were not responding optimally to current neuroleptic treatment (Silver A A et al. The Effects of Nicotine on Biological Systems II. P B S Clarke, M. Quik and K. Thurau, (Eds.); Advances in Pharmacological Sciences, Birkhauser Publishers, pp. 293-299, 1995). Patients' tics were videotaped before treatment began and 3 hours after the start of treatment. The frequency and severity of tics were reduced 47% and 34%, respectively, at three hours. Patients with the least control by neuroleptic treatment showed more dramatic improvement than did patients whose neuroleptic treatment alone had been more effective. The effects of the TNP persisted longer than the expected 24 hours. In two patients with incapacitating TS symptoms before the TNP, the effect lasted 3 weeks to 4 months without further administration of nicotine.
To further explore the potential long-term therapeutic response to TNP in TS patients, twenty TS patients (17 children and adolescents and 3 adults), in 18 of whose tic symptoms were not controlled with neuroleptics and 2 of whom were free of medication, were followed for various lengths of time following the application of two TNPs (Silver A A et al. J Amer Acad Child & Adolescent Psychiatry, 35(12): 1631-1636, 1996; Shytle R D et al. Drug Development Research, 38(3/4): 290-298, 1996). While there was a broad range of individual responses, it was determined that each application of a single TNP produced a significant reduction in Yale Global Tic Severity Scale mean scores lasting approximately 1-2 weeks. Thus, transdermal nicotine was an effective adjunct to neuroleptic therapy of TS, and helped when administered alone to two patients.
It has been observed that 50% of children presenting with TS also have Attention Deficit Hyperactivity Disorder (ADHD). ADHD is a neurobiological disorder characterized by impaired attentiveness, increased impulsivity, and hyperactivity. ADHD is now the most commonly diagnosed childhood psychiatric condition, with some 3.5 million afflicted. In addition, 60% of adolescents with ADHD continue to have symptoms in adulthood, representing another 2.5 million patients.
The current patent application is concerned with the administration of nicotine antagonists, particularly mecamylamine (3-methylamino-2,2,3-trimethylnorcamphane). Mecamylamine is well known as a nicotine antagonist and blocks ganglia which nicotine stimulates. First introduced as an anti-hypertensive, mecamylamine blocks sympathetic ganglia transmission and thereby causes vasodilatation and a fall in blood pressure (Taylor P, In: Goodman L S, Gilman A (eds) The Pharmacological Basis of Therapeutics, McMillan Publishing Co., New York City, pp. 193-95, 1996). Generalized ganglionic blockade may result also in atony of the bladder and gastrointestinal tract, impaired sexual function, cycloplegia, xerostomia, diminished perspiration and postural hypotension. While the clinical use of mecamylamine as a ganglionic agent has largely been replaced by more effective antihypertensive medications, scientists remain interested in mecamylamine because of its ability to block nicotine binding sites in the brain (see, e.g., Martin B R, Onaivi E S, Martin T J, Biochemical Pharmacology 38: 3391-3397, 1989; and Banerjee S et al, Biochemical Pharmacology 40(9): 2105-2110, 1990). These nicotine binding sites, known as nicotinic acetylcholinergic receptors (nAChr), are normally activated in the brain by acetylcholine, a prominent neurotransmitter.
Nicotine, via tobacco in various forms, has been one of the most widely utilized drugs for centuries (Wilbert J, J Ethnopharmacol 32(1-3): 179-186, 1991). Nicotine is a potent modulator of nAChrs (Changeux J P, Sci Amer (November) pp. 58-62, 1993). Through these receptors, nicotine activates the presynaptic release of several neurotransmitters including acetylcholine, norepinephrine, serotonin and dopamine (Balfour D J K, Pharmacological Therapeutics 16: 269-282 1982). Agents which can modulate central monoaminergic neurotransmissions by acting on nAChrs may be useful therapeutically for treating neuropsychiatric disorders (Jarvick M E, Br J Addict 86: 571-575, 1991; Newhouse P A, Hughes J R, Br J Addict 86: 521-526, 1991; and Hughes J, Clarke P B S (Eds): The effects of nicotine on biological systems II. Abstract S40, 1994; Decker M W et al, Life Sci 56: 545-570, 1995).
Unlike some ganglionic blocking agents, which do not readily reach the central nervous system (CNS), mecamylamine has been reported to produce central effects in humans, such as blocking the CNS actions of nicotine (Martin B R, Onaivi E S, Martin T J, Biochemical Pharmacology 38:3391-3397, 1989) and in altering cognitive functioning (Newhouse P A et al, Neuropsychopharmacology 10: 93-107, 1994), electrical brain waves (Pickworth W B, Herning R I, Henningfield J E, Pharmacology Biochemistry & Behavior 30: 149-153, 1988) and cortical blood flow (Gitalman D R, Prohovnik I, Neurobiology of Aging 13: 313-318, 1992).
While most animal studies used more than 0.5 mg/kg, Driscoll found that a small dose of only mecamylamine (&lt;0.3 mg/kg, not 0.5 mg/kg) to high-avoidance rats increased their avoidance success almost as much as 0.1 mg/kg nicotine (but less than 0.2 mg/kg nicotine). Based on his experiments, Driscoll concluded that "mecamylamine may exert unpredictable effects on rats at the dosage levels used to block nicotine in behavioral tests" (Driscoll P., Psychopharmacologia (Berl.) 46:119-21, 1976).
In a recent study of the nicotine receptor (nicotine binding site) and its ion channel (mecamylamine binding site), Banerjee et al. disclosed that mecamylamine and several nicotine analogs have a high affinity for the mecamylamine site. Like mecamylamine, several nicotine analogs also have anti-nicotinic effects (Banerjee S et al. Biochem Pharmacol 40(9): 2105-10, 1990). Research is also proceeding on alkaloids which act on the nicotinic receptor channels (Daly J W: Alkaloids as Agonists, Antagonists and Noncompetitive Blockers of Nicotinic Receptor Channels. In: Proceedings of Nicotinic Acetylcholine Receptors as Pharmaceutical Targets. Jul. 24-25, 1997, Washington, D.C.).
Many neuropsychiatric disorders involve abnormal or involuntary movements including but not limited to obsessive-compulsive disorder (OCD), TS, ADHD, hemidystonia, and Huntington's disease. These diseases may be caused by neurochemical imbalances in the brain's basal ganglia. Acetylcholine, by activating nAChrs in the basal ganglia, regulates motor activity in humans. The action of nAChrs in the basal ganglia has been well documented (Clarke P B S, Pert A, Brain Res 348: 355-358, 1985). Nicotinic stimulation excites activity in the dopamine (DA)-producing cells in the basal ganglia (Clarke P B S et al, J Pharmacol Exper Therapeutics 246: 701-708, 1988; Grenhoff J, Aston-Jones G, Svennson T H, Acta Physiol Scand 128: 351-358, 1986; Imperato A, Mulas A, Di Chiara G, Eur J Pharmacol 132: 337-338, 1986), while mecamylamine blocks nAChr and inhibits DA release from basal ganglia structures (Ahtee L, Kaakkola S, Br J Pharmacol 62: 213-218, 1978).
U.S. Pat. No. 5,774,052 to Rose and Levin discloses agonist-antagonist combinations to reduce the use of nicotine and other drugs. In combination with nicotine, the nicotinic antagonist mecamylamine was given to treat tobacco dependency. Rose and Levin proposed including both nicotine and mecamylamine in a patch. Rose and Levin also suggested that such agonist-antagonist combinations could be used in other psychopathological disorders and cases involving neuronal dysfunction (e.g., manic depression, schizophrenia and hypertension due to sympathetic autonomic disorder).
It would benefit patients to be able to have better symptom control and fewer side effects. In particular, it would be preferable to take a single drug, as did patients in at least some of the reports disclosed herein. Our clinical experience with mecamylamine in human patients with a variety of diagnoses supports a variety of uses. Herein is disclosed improved symptom control with a nicotine antagonist (mecamylamine) alone or in combination with neuroleptics for the treatment of a variety of nicotine-responsive neuropsychiatric disorders.